Spiropyranopyridines

ABSTRACT

THE PRESENT INVENTION IS CONCERNED WITH SPIROPYRANOPYRIDINES OF FORMULA I:   5,6-(-Z-)(-R4),4-R2,3-R5,1&#39;&#39;-R1,3&#39;&#39;,4&#39;&#39;-(-Y-)(-R3)-   SPIRO(4H-PYRAN-2(3H),2&#39;&#39;-PIPERIDINE)   WHEREIN Y AND Z ARE AROMATIC OR HETEROAROMATIC NUCLE, R1, R2, R3, R4 AND R5 ARE HYDROGEN OR VARIOUS SUBSTITUENTS SUCH AS ALKYL, ARYL, ALKOXY, HALOGEN, ETC.

United States Patent U.s. or. 260-287 R 1 Claim ABSTRACT OF THE DISCLOSURE The present invention is concerned with spiropyranopyridines of Formula I:

wherein Y and Z. are aromatic or heteroaromatic nuclei, R R R R and R are hydrogen or various substituents such as alkyl, aryl, alkoxy, halogen, etc.

The compounds of this invention are useful as antiarrhythmic agents.

The present invention relates to spiropyranopyridines having the following structural formula:

wherein Y and Z are aromatic or heteroaromatic nuclei; R R and R are hydrogen, lower alkyl, aryl, acyl or aralkyl, R and R are hydrogen, lower alkoxy, lower alkyl, aryl, aralkyl, amino, hydroxy, acetyl, nitro, or halogen.

As used in this disclosure, the term halogen comprehends all four halogens, i.e., chlorine, bromine, iodine, and fluorine. The term lower alkyl as used herein includes lower aliphatic hydrocarbons having 1 to 7 carbon atoms in the carbon chain. It includes straight chain as well as branched chain radicals. This term includes, for example, methyl, ethyl, propyl, isopropyl and the like. The term aryl as used in this disclosure denotes a monocyclic hydrocarbon radical, preferably of 6 to '10 carbon atoms, such as phenyl, tolyl, and the like.

"The term aryl also' includes aromatic or heteroaromatic .lower alkyl, groups in which an aryl group as defined above is substituted for a hydrogen atom, such as for example, benzyl, phenethyl or the like and also includes such groups wherein one or more of the hydrogen atoms of the phenyl portion haverbeen substituted by a functional group as indicated above. The term aromatic 3,649,635 Patented Mar. 14, 1972 ice or heteroaromatic includes a group such as benzene, naphthalene, phenanthrene, pyridine, quinoline, isoquinoline, pyrrole, indole, carbazole and the like. The term acyl are those hydrocarbon carboxylic acids as exemplified by the lower alkanoic acids and the monocyclic aryl carboxylic acids, for example, benzoic and toluic, and the monocyclic aryl lower alkanoic acids, for example, phenacetic and the like.

The compounds of this invention exhibit antiarrhythmic properties in several mammalian species, for example, beagle dogs, cats, and the like, for example, at a dose of about 3 to 5 mg./kg. intravenously. They are eifective in oubain induced arrhythmia in beagle dogs. They are useful in the treatment of cardiac arrhythmia. Generally speaking, a dosage level of 3 to 5 mg./kg. orally, or by injection, two or three times a day is prescribed to treat cardiac arrhythmias. This dose level can be varied according to the species of mammal being treated and also the age, weight, sex, and the severity of the condition of the mammal.

In order to use these compounds, they are combined with pharmaceutically acceptable excipients, for example, lactose, decalcium phosphate, and granulated with suitable granulating agents, such as water, alcoholic gelatin solution and the resulting granules are compressed into tablets. Other known pharmaceutical dosage forms, such as pills, capsules, elixirs can also be compounded according to methods well known to the pharmacists art. For parenteral use, the compounds of this invention are suspended or dissolved in a parenterally acceptable vehicle, such as saline, water for injection, sesame oil and the like,

According to the present invention, the spiropyranopyridines are prepared from phenolic Mannich bases of the Formula III:

(III) and partially reduced heteroaromatic compounds of the Formula II:

car 11) wherein R and R are lower alkyl, aryl, aralkyl, or taken together with the nitrogen atom to which they are attached from a pyrrole, morpholine, piperidine or piperazine ring.

Compounds of Type II are prepared by standard methods such as described by F. Bohlmann in Chemische Berichte, 100, 2742 (1967). Compounds of Type III are available from commercial sources and can be prepared by standard procedures, described in ct-Aminoalkylierung by Hellmann and Opitz, Verlag Chemie GmbH, Weinheim, Germany (1960).

The following examples are included in order further to illustrate the invention.

EXAMPLE 1 1,2,3,4-tetrahydro-2-methyll-phenylspiro 3'H-naphtho- [2, 1-b]pyran-3,l (2H)pyrido [3,4-b] indole] A solution of 10 g. of 1-methyl-3,4-dihydro-p-carboline methiodide in 600 ml. of boiling H is made strongly basic with 40% NaOH. The mixture is chilled, and extracted with three 150 ml. portions of ether. Combined ether and extracts are dried over Na SO and taken down to a gum under reduced pressure. The gum is dissolved in 30 ml. of dioxane, 8.31 g. of 1-(2-dimethylatnin0benzyl)-2-naphthol is added, and the solution is refluxed under a stream of nitrogen for 3 hours. A heavy crystalline precipitate forms. The reaction mixture is chilled, and the crystals are filtered off, and recrystallized from CH CN; M.P. 197200 C.; yield 8 g. (62%).

Analysis.Calcd. for C H N 0 (percent): C, 83.69; H, 6.09; N, 6.51. Found (percent): C, 83.65; H, 6.06; N, 6.41.

EXAMPLE 2 1,2,3 ,4-tetrahydro-2-methylspiro 3H-naphtho- [2,1-b]pyran-3,l (2H)-pyrido[3,4-b]indole] A solution of g. of 1-methyl-3,4-dihydro-B-carboline -CH I in 600 m1. of boiling H O is made strongly basic with 40% NaOH. The chilled mixture is then extracted with three 150 ml. portions of ether. The combined ether extracts are dried over Na SO and taken down. to a gum under reduced pressure. The gum is dissolved in ml. of dioxane, 6 g. of 1-dimethylaminomethyI-Z-naphthol is added, and the solution is refluxed under a stream of nitrogen for 3 hours. The solution is cooled, and the crystalline precipitate that forms is filtered off, washed with dioxane, and recrystallized from ethyl acetate with the aid of charcoal, M.P. 178-181 C.; yield 4 g. (38%).

Analysis.Calcd. for C H N O (percent): C, 81.32; H, 6.26; N, 7.90. Found (percent): C, 81.26; H, 6.40; N, 7.85.

EXAMPLE 3 1,2,3,4-tetrahydro 2 methylspiro[3H-pyrano[3,2-f] quinoline 3 ,1 (2H) pyrido [3,4-b] indole] dihydrochloride hemiethanolate A solution of 10 g. of 1-methyl-3,4-dihydro-p-carboline methiodide in 600 ml. of boiling H 0 is made strongly basic with 40% NaOH. The mixture is chilled and extracted with three 150 ml. portions of ether. Combined ether extracts are dried over Na SO and taken down to a gum under reduced pressure. The gum is dissolved in 30 ml. of dioxane, 6 g. of 5-[(dimethylamino)methyl]-6- quinolinol is added, and the solution is refluxed under a stream of nitrogen for 2 hours. A heavy precipitate forms in the reaction mixture. The mixture is cooled, the crystals are filtered off, washed with cold dioxane, and dissolved in 100 ml. of hot 1 N HCl. On cooling, crystals deposit. These are filtered and recrystallized from aqueous ethanol, M.P. 271-277 C.; yield 9 g.

Analysis.-Calcd. for C H N 'O'2HCl' /2C H O H (percent): C, 63.86; H, 5.80; N, 9.31; Cl, 15.71. Found (percent): C, 63.77; H, 5.67; N, 9.39; CI, 15.81.

EXAMPLE 4 1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylspiro[isoquioline-l 2H) ,3 (3H) pyrano[ 3,2-t quinoline] A solution of 2.19 g. of l,2,3,4-tetrahydro-6,7-dimethoxy-2-methy1-l-methylene isoquinoline and 2 g. of S-(dimethylaminomethyl)-6-quinolinol in 10 ml. of dioxane is refluxed under a stream of nitrogen for 45 minutes. The solution is chilled, and the crystalline precipitate that forms is filtered off, washed with cold dioxane, and recrystallized from CH CN, M.P. 178-179" C.; yield 1 g. (26%).

Analysis.-Calcd. for C H N O (percent): C, 73.38; H, 6.43; N, 7.44. Found (percent): C, 73.59; H, 6.63; N, 7.47.

EXAMPLE 5 Ethyl 3,4,8',9'-tetrahydro 6,7 dimethoxy-2,2'-dimethylspiro[isoquinoline 1(2H),7(7H),-[3H]pyrano[3,2-e] indolell carboxylate A solution of 8.8 g. of 1,2,3,4-tetrahydro-6,7-dimethoxy- 2-methy1-1-methyleneisoquinoline and 11 g. of ethyl 6-hydroxy 5 (dimethylaminomethyl) 2 meth'ylindole-3- carboxylate in 40 ml. of dioxane is refluxed for 1.5 hr. under a stream of nitrogen. The dioxane is removed under reduced pressure and the residue is recrystallized from absolute ethanol, M.P. 176-1775 C.; yield 5 g. (28% Analysis.-Calcd. for C H N O (percent): C, 69.31; H, 6.71; N, 6.22. Found (percent): C, 69.24; H, 6.94; N, 6.16.

EXAMPLE 6 OCH 1,2,3 ,4 tetrahydro 6',7-dimethoxy-2-methylspiro 1 1H- 1-benzopyrano[5,6-b] indole-3(3H)-1(2H)-isoquinoline] This is prepared from 9.6 g. of l-(dimethylamino-Z- hydroxymethyDcarboxazol, and 8.8 g. of l,2,3,4tetrahyd.r0-6,7-dimethoxy 2 methyll-meth'yleneisoquinoline in analogous fashion to 1,2',3,4-tetrahydro-2-methylspiro [isoquinoline-1(2H) ,3 (3 H)-naphtho[2,1-b]pyran] The material is recrystallized from ethyl acetate, M.P. 134- 139 C.; yield 2 g. (12%).

Analysis.-Calcd. for C H N O (percent): C, 75.34; H, 6.32; N, 6.76. Found (percent): C, 75.14; H, 6.34; N,

EXAMPLE 7 l CH3 1,2,3 ,4-tetrahydro-2-methylspiro[isoquinoline- 1(2H) ,3 (3H) pyrano[3,2-f] quinoline] A solution of 6.4 g. of 1,2,3,4-tetrahydro-2-methyl-1- methyleneisoquinoline and 8 g. of S-(dimethylaminomethyl)-6-quinolinol in 40 m1. of dioxane is refluxed under a stream of nitrogen for 1.5 hr. The mixture is chilled and the heavy crystalline precipitate is filtered off and recrystallized from ethanol, M.P. 164167 0.; yield 8 g. (63%).

Analysis.Caled. for C H N O (percent): C, 79.71; H, 6.37; N, 8.85. Found (percent): C, 79.93; H, 6.39; N, 8.63.

EXAMPLE 8 O l 08 o l',2',3 ,4-tetrahydro-2-methyl-1'-phenylspiro [isoquinoline-1-(2H) ,3(3'H)-naphtho[2,1-b1pyran] This is prepared from 13.7 g. of l-(a-dimethylaminobenzyl)-2-naphthol and 8 g. of 1,2,3,4-tetrahydro-2-methyl-l-methyleneisoquinoline in analogous fashion to 1',2', 3,4 tetrahydro 2 methylspirofisoquinoline 1(2H), 3'(3'H)-naphtho[2,1-b]pyran]. The material is recrystallized from ethyl acetate, M.P. 172173 C.; yield 8 g. (43

Analysis.-Calcd. for C H NO (percent): C, 85.90;

6 H, 6.44; N, 3.58. Found (percent): C. 85.73; H, 6.39; N, 3.40.

EXAMPLE 9 8 '-bromo- 1',2', 3,4-tetrahydro-Z-methylspiro [isoquinoline- 1(2H),3(3'H)-naphtho[2,1-b]pyran] This is prepared from 2 g. of 6-bromo-1-(dimethylaminomethyl) i 2 naphthol, and 1.14 g. of 1,2,3,4- tetrahydro 2 methyl 1 methyleneisoquinoline in analogous fashion to 1,2',3,4 tetrahydro 2 methylspiro[isoquinoline 1(2H),3'(3'H) naphtho[2,1 b] pyran]. The material is recrystallized from CH CN, M.P. 171-1735 0; yield 2 g. (71.5%).

Analysis.-Calcd. for C H BrNO (percent): C, 67.01; H, 5.11; N, 3.55. Found (percent); C, 67.18; H, 5.07; N, 3.73.

EXAMPLE 10 'dimethylspiro [isoquinoline 1 (2H) ,7 7H) ,-[3H] pyrano- [3,2-e] indo1e]-1'-carboxylate.

References Cited UNITED STATES PATENTS 12/1970 Von Strandtmann 260287 5/1971 Von Strandtmann 260288 OTHER REFERENCES Bobranski et al., abstracted in Chem. Abstr. vol. 61, col. 4310b (1964).

DONALD G. DAUS, Primary Examiner U.S. Cl. X.R.

260283 R, 286 R, 288 R, 289 R, 296 PYC 326.14; 424258, 263, 274 

